Diabetes is a burgeoning, worldwide health problem affecting almost twenty-six million people in the United States, with obesity-associated type II diabetes (T2D) accounting for ninety-five percent of all diabetes cases. To date, two bile acids (BAs) receptors have been identified: the nuclear farnesoid X receptor (FXR) and the Takeda G-protein-coupled Receptor 5 (TGR5). TGR5 is a cell surface receptor and expressed in monocytes, gall bladder, brown adipose tissue, muscle, liver, and intestine. Its activation by BAs triggers an increase in energy expenditure and attenuates diet-induced obesity. TGR5 activation by BAs, may regulate glucose homeostasis and insulin sensitivity.
Endogenous BAs are the physiological ligands of TGR5 but are, however, very weak TGR5 ligands in the context of both potency and specificity. BAs not only activate TGR5, but also trigger activation of the nuclear receptor FXR. Thus, the identification of selective and potent modulators for TGR5 with enhanced efficacy is of crucial and significant value. Provided herein are solutions to these and other problems in the art.